PROJECT SUMMARY/ABSTRACT: Over the past two decades there has been a worldwide increase in the prevalence of obesity. In the United States 60% of the population is either overweight or obese. As a result, rates of obesity related co-morbities, particularly type II diabetes are increasing. Furthermore due to rising rates of obesity in the young, type II diabetes is now seen even in adolescence patients. This creates a demand for more and better therapeutic agents, potentially focused on novel pathways. Recently, FGF21 has emerged as a hepatic regulatory factor that acts on multiple remote targets including white adipose tissue but importantly also mediates effects on the liver itself in an autocrine fashion. We have found that FGF21 is an essential mediator of fatty acid oxidation in the liver, during ketosis, both in animals consuming a very low carbohydrate ketogenic diet and during fasting; others have reported improvements in glucose homeostasis in obese animals treated with FGF21 infusions. However, much remains to be elucidated regarding the biology of FGF21. The aims of this grant are to investigate the physiology and action of FGF21 both to improve our understanding of this hormone and to better assess the therapeutic potential of FGF21 as a future treatment of obesity and diabetes. To achieve this goal, we propose several lines of experimentation. In specific aim 1 we will evaluate the role FGF21 to regulate both glucose homeostasis and fatty acid oxidation during fasting. In addition we will generate two mouse models to determine the role of FGF21 in different tissues. In the second aim we will expand our work on obesity as FGF21 resistant state by exploring potential mechanisms that contribute to resistance which we have documented in both fat and liver. In this aim we will also evaluate the role of dual specificity phosphatases (DUSPs) in modulating FGF21 action. In the third specific aim we will focus on our recent finding that FGF21 acts on both brown adipose tissue and white adipose tissue in a manner suggesting a role to promote energy expenditure. In the fourth aim we will examine central effects of FGF21 and map target areas of the CNS that mediate these effects.